Total knee arthroplasty (TKA) is an increasingly common surgical procedure in older adults. Although effective for many patients, 15% or more experience unsatisfactory pain outcomes. While limited to post- surgical chronic pain in some patients, others also develop regional allodynia and hyperalgesia, edema, and autonomic features indicating Complex Regional Pain Syndrome (CRPS), a particularly difficult to treat chronic pain condition. The mechanisms of post-TKA chronic pain and CRPS are not well understood. The most common TKA procedure involves application of a tourniquet to the operated limb for extended periods (up to ?2 hours). Animal models indicate that extended tourniquet application followed by reperfusion when the tourniquet is removed leads to ischemic reperfusion injury, which via increased oxidative stress, can result in prolonged neuropathic pain and clinical features of CRPS. One key objective of this project is to examine for the first time in humans the impact of baseline and perioperative oxidative stress, as indexed by F2- isoprostanes, on long-term pain, CRPS, and functional outcomes following TKA. One known predictor of post- TKA chronic pain is greater preoperative negative affect (specifically, depression and anxiety). Emerging literature suggests that elevated depression and anxiety may be associated with elevated oxidative stress levels. The proposed project will test a novel theoretical model that integrates these disparate research areas by determining whether the influence of depression and anxiety on post-TKA chronic pain outcomes is conveyed in part through oxidative stress mechanisms. If hypotheses are supported, results will highlight a novel mechanism of post-surgical chronic pain and CRPS that is potentially amenable to pre-emptive intervention, and enhance understanding of mechanisms through which psychosocial factors impact on subsequent postsurgical pain-related and functional outcomes. The project team will be comprised of investigators with complementary multidisciplinary expertise in chronic pain, CRPS, measurement and health effects of oxidative stress, TKA procedures, and prospective study designs. The proposed study will enroll 150 unilateral TKA patients all experiencing similar tissue trauma during the course of surgery. Pain, CRPS symptomatology (using a validated continuous CRPS severity score), depression and anxiety symptoms, function, and plasma levels of F2-isoprostanes will be systematically assessed at pre-TKA baseline, intraoperatively, for two days post-surgically, and at 6 week and 6 month follow-up. Analyses will utilize the prospective nature of the data to examine the impact of baseline and perioperative oxidative stress on subsequent chronic pain, CRPS, and functional outcomes. Mediation analyses will be used to test whether depression and anxiety impact on long-term post-TKA pain, CRPS, and function in part via oxidative stress mechanisms. Results have the potential to enhance understanding of the mechanisms of post-surgical chronic pain and CRPS, and guide development of mechanism-based preventive interventions for both.